Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of dysphoria, and KOR activation by agonists or by stress-evoked dynorphin release in rodents produces aversion. These dysphoric/aversive effects of KOR activation have been shown to increase the rewarding effects of cocaine, increase drug self-administration, and reinstate extinguished drug seeking behaviors. The cellular and molecular mechanisms responsible for KOR-dependent aversion are not fully understood, but a better understanding may suggest new therapeutic approaches to the treatment and prevention of stress-related diseases including some forms of drug addiction. Evidence strongly supports a role for KOR-dependent inhibition of dopamine release in the nucleus Accumbens (NAc), however recent evidence further suggests that dynorphin activation of p38 MAPK in the serotonergic dorsal raphe nucleus (DRN) is also required for KOR-dependent aversion. Because a complementary role of serotonin in the regulation of affective state seems plausible, we propose to understand how activation of p38 MAPK by KOR stimulation, either by stress-induced dynorphin release in the DRN or systemic administration of a selective KOR agonist, results in conditioned place aversion. To accomplish these aims we propose 1) to measure KOR-dependent aversion in conditional knockout (CKO) mice having floxed p38a MAPK excised by PET1-promoter driven Cre recombinase, 2) to assess the effects of p38a MAPK activation by KOR on serotonin transporter reuptake efficiency in synaptosomes prepared from swim stressed mice having either normal or genetically modified dynorphin/KOR system function, and 3) to measure the effects of KOR- dependent p38 MAPK activation on electrically evoked release of serotonin and dopamine in vivo and in brain slices using fast scan cyclic voltammetry. Our hypothesis is that the aversive effects of KOR activation is a consequence of a shift in the balance between serotonergic and dopaminergic tone in the NAc caused by p38a MAPK activation of the serotonin transporter. PUBLIC HEALTH RELEVANCE: Although the stress response is generally protective, repeated and uncontrollable stress exposure can increase the risks of mood disorders and drug addiction. The mechanisms underlying these adverse effects need to be understood before better treatments for stress- related diseases can be developed. Activation of the dynorphin/kappa opioid systems in brain has been shown to encode the dysphoric effects of stress. The proposed studies would test the hypothesis that dynorphin activation of KOR increases p381 MAPK activity in serotonergic neurons projecting from DRN to NAc and that activation of the serotonin transporter by p38 mechanisms contributes to the aversive response following KOR activation.